This proposal focuses on the generation, control, and exploitation of diversity in biology. Genetic diversity drives the evolution of organisms, hinders cures of cystic fibrosis, AIDS and cancer, plays a crucial role in bacterial and fungal infections, and accounts for individual differences in susceptibility to disease agents and the responses to drugs. Non-genetic diversity allows different cells to respond differently to the same environment, differences that can increase the infectivity of pathogens and their resistance to antibiotics. This team will use experiment and theory to study the origin and consequences of biological diversity over scales of size and time that range from the folding of individual proteins to the formation of new species. The goals of the research are: 1) Generating diversity: We will define the rate at which organisms generate diversity. We will determine the distribution of beneficial and deleterious mutations and assess the role of specialized forms of mutation. We will determine the maximum accuracy of regulatory circuits. 2) Controlling diversity: We will study how organisms control the effect of noise. The numbers of copies of any molecule in a cell fluctuates stochastically and cells must deal with errors that produce damaged molecules. We will investigate how evolution and engineering can minimize the effects of noise in processes as diverse as protein folding, gene expression, and circadian clocks. 3) Responding to environmental diversity: Organisms must optimize their response to temporally and spatially variable environments. We will investigate the ability of existing pathways to detect fluctuating environments and examine how organisms evolve to respond to them, 4) Exploiting diversity: We will investigate how selection acts on genetic diversity to produce new phenotypes. We will ask how selection produces a range of biological phenomena, including altered patterns of gene expression, alterations in the host range and social behavior of pathogens, new species, and stable community structures in ecosystems. The core of the proposal is the group of Bauer fellows, young interdisciplinary scientists who come from a variety of backgrounds and interact to form a single collaborative community that nucleates interactions amongst a wide range of research groups.